Extracellular ATP acts as a neurotransmitter and modulator of cellular function by binding to and activating two classes of cell surface receptors: P2X ion channels and P2Y G protein-coupled receptors. The signaling function of ATP, ADP, UTP, UDP, UDP-sugars and other nucleotides by activating P2Y receptors is increasingly viewed as new, fertile ground for drug discovery, because of the important influence of these receptors on cell proliferation and death, release of cytokines and activation of immune responses, stem cell differentiation, communication at the tripartite synapse in the brain, and many other functions. The modulatory effect of these nucleotides alters the set point of an organ, by analogy to a radio, it adjusts the volume knob rather than the on/off switch. Adjusting the level of receptor action ideally does not prevent the essential role of these receptors in the normal tissue. Thus, critical functions of these receptors are either up- or downregulated depending on a disease state and subject to control by the administration of selective, receptor subtype-selective ligands. This class of receptors is responsible for maintaining homeostatis in a variety of organ systems, and their pharmacological manipulation is especially relevant to chronic disease states such as inflammation, digestive disorders, neurodegeneration, endocrine disorders and cardiac failure. The challenge to the medicinal chemist is both to enhance selectivity of the nucleotide derivatives within the family of eight P2Y receptor subtypes and to enhance the stability and bioavailability of normally unstable native ligands. The introduction of numerous selective agonists and antagonists of P2Y receptors (P2YRs) by our laboratory, and their availability for use as pharmacological research tools, has greatly facilitated research in this area. Exploration of the role of P2YRs in large part using our ligands (given the number designation MRS, after the Molecular Recognition Section) has led to the introduction of new therapeutic concepts, such as use of P2Y1R antagonists as antithrombotic agents, P2Y6R agonists or P2Y13R antagonist for treatment of diabetes, and P2Y14R antagonists for asthma. For example, we have explored in detail the signaling pathways related to the action of UDP on pancreatic beta islet cells, including preventing apoptosis and promoting insulin release. Many of the known ligands for the P2YRs are notoriously unstable when administered in vivo due to the labile phosphate moiety. In order to explore new drug concepts for the P2YR, it is necessary to improve upon the bioavailability and stability of the compounds either by nucleotide modification or by searching for chemically diverse, preferably uncharged, ligands. Both of these efforts are being carried out in our laboratory using molecular modeling and organic chemical synthesis. Virtual screening has identified compound leads for novel antagonists of the P2Y1R and other subtypes. We have also achieved the structure-functional analysis of various P2YRs, by indirect means, using mutagenesis and molecular modeling based on other GPCR templates, because crystallographic structural determination is not yet available. Our selective ligands for various P2YRs have recently made possible the identification of new therapeutic directions, such as P2Y1 antagonists as antithrombotics, P2Y2 agonists for cardioprotection, and P2Y6 ligands for neurodegenerative diseases and skeletal muscle protection. We designed and synthesized new agonists of the P2Y6 nucleotide receptor using classical and computational approaches. The most potent of these agonists, UDP analogue MRS2795, contains a methanocarba ring system in place of the ribose moiety, which was prepared as a pure stereoisomer using a novel synthetic route. This ring system is locked in the South (S) envelope conformation, which is greatly preferred over other conformations in agonist recognition at the P2Y6R. Thus, the conformational requirements of the ribose moiety of UDP analogues in binding to the P2Y6R are very different from those of the P2Y1R, which prefers a North (N) conformation. We also designed and synthesized the first selective agonist of the P2Y4R MRS4062, a N4-oxoimino derivative of CTP, and defined a new hydrophobic binding region of the P2Y4R. Additionally, we carried out the first systematic SAR studies on the P2Y14R leading to compounds of nanomolar affinity, such as the agonist MRS2905, a UDP analogue. A uracil nucleoside phosphonate MRS2802 is being explored as a P2Y2R allosteric agonist. In summary, we emphasize four aspects of studying the P2Y receptors: 1) design and synthesis of novel and selective agonists and antagonists based on SAR; 2) structure-function studies of the receptor proteins; 3) exploring the novel biological role of such receptors; and 4) conceptualization of future therapeutics. In this effort, there is a tight coupling of organic synthetic methodology, structural biology, and pharmacology.